The long-term goal of this research project is to develop a class of integrated miniature microscopes that utilize the interaction of light with tissues in many modalities to image morphology and biochemistry in vim, yielding tools that provide better delineation of tumors. We envision the eventual development of battery-powered, pen-sized multi-modal miniature microscopes (4Ms) designed to specifically image microscopic and molecular features of pre-cancer. The proposed miniature microscopes are dubbed multi-modal because of their potential for enabling different imaging modalities such as optical sectioning, three-dimensional (3D) spectral fluorescence imaging, and reflectance imaging. We believe that the cost and size of these microscopes can eventually be made small enough to enable broad use and applicability in many organ sites. Because of the easy accessibility of the oral cavity and uterine cervix, we will first test these tools in detection of pre-cancers in these organ sites. Successful development of a 4M device requires concurrent and tightly coupled advances in: (1) fabrication and assembly of micro-optical systems, (2) development of micro-mechanical devices, and (3) development of complementary metal-oxide semiconductor (CMOS) active-pixel image sensors. Within the scope of this R21/R33 proposal, we will construct prototype 4M devices that include a custom CMOS active-pixel image sensor, a set of lithographically fabricated optical elements, and a micro-mechanical scanning grating that enables optical sectioning of 3D specimens through structured illumination. The constructed 4M devices will be optimized for reflectance imaging at 800 nm ("Red 4M device") and autofluorescence imaging ("Blue 4M device"). We will demonstrate 4M-device feasibility on an NA = 0.4, monochromatic Red 4M device. Next, we will construct an enhanced NA= 0.6 Red 4M device and a polychromatic NA = 0.4 Blue 4M device. This series of 4M devices will establish the technology base from which to construct future 4M devices optimized for imaging with new contrast agents. Testing of all constructed 4M devices will be carried out on: (1) organotypic cultures and short-term tissue cultures of normal and neoplastic cervix, (2) organotypic cultures and short-term tissue cultures of normal and neoplastic oral-cavity, and (3) animal models.